Effect of HRT on Cardiovascular Events
Effect of HRT on Cardiovascular Events
Objective To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women.
Design Open label, randomised controlled trial.
Setting Denmark, 1990-93.
Participants 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone.
Interventions In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.
Main outcome measure The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction.
Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer.
Conclusions After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.
Trial registration ClinicalTrials.gov NCT00252408.
Hormone replacement therapy for postmenopausal women has been subject to much discussion and speculation since the 1960s. Before 2002 the effects of hormone replacement therapy were believed to be beneficial, owing to a reduction in risk of cardiovascular disease, osteoporosis, and colon cancer. The negative side effects—an increased risk of breast cancer and thromboembolic disease—were thought to be outweighed by the advantages, principally on the basis of results from observational studies. In 2002 the primary results from the Women’s Health Initiative showed no cardiovascular benefit from hormone replacement therapy. These conflicting results have led to the “timing hypothesis”; the idea that the differences in cardiovascular outcome can be accounted for by time since menopause until the start of hormone therapy. The observational studies mainly have shown positive cardiovascular effects, probably as a result of hormone therapy starting shortly after menopause, and the randomised studies have shown no or negative cardiovascular effects, often in women who start hormone therapy many years (5 to 20) after menopause. In meta-analyses taking age into special consideration, use of hormone therapy in younger women has been associated with a lower risk of coronary heart disease and reduced overall mortality.
We used data from the Danish Osteoporosis Prevention Study (DOPS) to test whether hormone replacement therapy can reduce cardiovascular endpoints in women if started early after menopause.
Abstract and Introduction
Abstract
Objective To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women.
Design Open label, randomised controlled trial.
Setting Denmark, 1990-93.
Participants 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone.
Interventions In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.
Main outcome measure The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction.
Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer.
Conclusions After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.
Trial registration ClinicalTrials.gov NCT00252408.
Introduction
Hormone replacement therapy for postmenopausal women has been subject to much discussion and speculation since the 1960s. Before 2002 the effects of hormone replacement therapy were believed to be beneficial, owing to a reduction in risk of cardiovascular disease, osteoporosis, and colon cancer. The negative side effects—an increased risk of breast cancer and thromboembolic disease—were thought to be outweighed by the advantages, principally on the basis of results from observational studies. In 2002 the primary results from the Women’s Health Initiative showed no cardiovascular benefit from hormone replacement therapy. These conflicting results have led to the “timing hypothesis”; the idea that the differences in cardiovascular outcome can be accounted for by time since menopause until the start of hormone therapy. The observational studies mainly have shown positive cardiovascular effects, probably as a result of hormone therapy starting shortly after menopause, and the randomised studies have shown no or negative cardiovascular effects, often in women who start hormone therapy many years (5 to 20) after menopause. In meta-analyses taking age into special consideration, use of hormone therapy in younger women has been associated with a lower risk of coronary heart disease and reduced overall mortality.
We used data from the Danish Osteoporosis Prevention Study (DOPS) to test whether hormone replacement therapy can reduce cardiovascular endpoints in women if started early after menopause.
